Potent in Vitro and In Vivo Efficacy of Hdz-C123A, a GSPT1 Degrader-Antibody Conjugate Targeting CD123 in Acute Myeloid Leukemia

Introduction:

Antibody-drug conjugates (ADCs), as an emerging class of targeted therapies, have garnered significant attention in cancer treatment due to their clinical potential in recent years. Currently, most ADC payloads are cytotoxic agents, prompting the need for novel payloads. Given the catalytic mechanism of action and expanded targeting capabilities, degraders are considered potential candidates for the next-generation payloads. We identified a potent and conjugable GSPT1 degrader CDG0501 through our Rosetta For Molecule Glue (RFMG) model and CRBN-based degrader library. Considering CD123 is a cell surface protein overexpressed in several hematologic malignancies, including AML and myelodysplastic syndrome (MDS), with restricted expression in normal hematopoietic stem cells, CDG0501 was conjugated to a humanized IgG1 targeting CD123 via a tumor-enriched protease-cleavable linker, resulting in HDZ-C123A, a stable and homogeneous conjugate with a drug-to-antibody ratio of 8. After a series of evaluations, HDZ-C123A has been validated as a promising pre-clinical candidate for further clinical development.

Results:

1. CDG0501 showed sub-nanomolar to nanomolar activity against multiple acute myeloid leukemia (AML) and non-Hodgkin lymphoma (NHL) cell lines.

2. In CD123-expressing cell lines, HDZ-C123A exhibited picomolar proliferative inhibition activity, which was 20-1000 times more potent than several GSPT1 degraders, including CC-90009, and showed robust activity in Mylotarg-resistant cell lines. Ex vivo experiments revealed a stronger potency of HDZ-C123A in AML patient-derived blasts compared to CC-90009 and venetoclax.

3. HDZ-C123A demonstrated minimal toxicity to peripheral blood mononuclear cells derived from healthy subjects, highlighting the potential of conjugation strategies to improve degraders' narrow therapeutic index.

4. HDZ-C123A showed significant anti-tumor efficacy and safety in several hematologic xenograft models and patient-derived models following single-dose administration. Particularly in the MV4-11 xenograft model, complete response was observed at doses as low as 1 mg/kg, Pharmacodynamic studies demonstrated that tumor growth inhibition correlated with the abundance of GSPT1 and related biomarkers.

Conclusions:

In summary, CDG0501, as a potent GSPT1 degrader, demonstrates potential as a next-generation payload in preclinical studies. HDZ-C123A, constructed based on CDG0501, shows promising potential as a first-in-class CD123-targeting degrader-antibody conjugate for AML treatment.

No relevant conflicts of interest to declare.